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High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice : Impact on Cognitive Function

de Oliveira, Jade ; Engel, Daiane F ; de Paula, Gabriela C LU ; Dos Santos, Danúbia B ; Lopes, Jadna B ; Farina, Marcelo ; Moreira, Eduardo L G and de Bem, Andreza F (2020) In Journal of Alzheimer's disease : JAD 78(1). p.97-115
Abstract

BACKGROUND: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia.

OBJECTIVE: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/-mice.

METHODS: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/-mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice's prefrontal cortices and... (More)

BACKGROUND: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia.

OBJECTIVE: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/-mice.

METHODS: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/-mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice's prefrontal cortices and hippocampi.

RESULTS: A tenfold elevation in plasma cholesterol levels of LDLr-/-mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr-/-mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr-/-mice treated with a hypercholesterolemic diet. The LDLr-/-mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr-/-mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice.

CONCLUSION: Therefore, LDLr-/-mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Blood-Brain Barrier, Cholesterol/metabolism, Cognition, Cognitive Dysfunction/metabolism, Diet, Disease Models, Animal, Gliosis/metabolism, Hippocampus/metabolism, Hypercholesterolemia/metabolism, Male, Memory, Memory Disorders/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Prefrontal Cortex/metabolism, Receptors, LDL
in
Journal of Alzheimer's disease : JAD
volume
78
issue
1
pages
97 - 115
publisher
IOS Press
external identifiers
  • pmid:32925052
  • scopus:85095114794
ISSN
1387-2877
DOI
10.3233/JAD-200541
language
English
LU publication?
no
id
1edbaa26-70d6-46c6-94d1-a1f057d49a94
date added to LUP
2021-09-21 19:47:35
date last changed
2024-06-16 19:17:14
@article{1edbaa26-70d6-46c6-94d1-a1f057d49a94,
  abstract     = {{<p>BACKGROUND: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia.</p><p>OBJECTIVE: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/-mice.</p><p>METHODS: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/-mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice's prefrontal cortices and hippocampi.</p><p>RESULTS: A tenfold elevation in plasma cholesterol levels of LDLr-/-mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr-/-mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr-/-mice treated with a hypercholesterolemic diet. The LDLr-/-mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr-/-mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice.</p><p>CONCLUSION: Therefore, LDLr-/-mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.</p>}},
  author       = {{de Oliveira, Jade and Engel, Daiane F and de Paula, Gabriela C and Dos Santos, Danúbia B and Lopes, Jadna B and Farina, Marcelo and Moreira, Eduardo L G and de Bem, Andreza F}},
  issn         = {{1387-2877}},
  keywords     = {{Animals; Blood-Brain Barrier; Cholesterol/metabolism; Cognition; Cognitive Dysfunction/metabolism; Diet; Disease Models, Animal; Gliosis/metabolism; Hippocampus/metabolism; Hypercholesterolemia/metabolism; Male; Memory; Memory Disorders/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Prefrontal Cortex/metabolism; Receptors, LDL}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{97--115}},
  publisher    = {{IOS Press}},
  series       = {{Journal of Alzheimer's disease : JAD}},
  title        = {{High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice : Impact on Cognitive Function}},
  url          = {{http://dx.doi.org/10.3233/JAD-200541}},
  doi          = {{10.3233/JAD-200541}},
  volume       = {{78}},
  year         = {{2020}},
}